A CUTE DECOMPENSATED HEART failure (ADHF) remains a common cause of hospitalization worldwide but it is not clear how patients admitted for clinical deterioration should be managed. Patients are generally treated with diuretics and vasodilators, while patients with evidence of peripheral hypoperfusion also may receive positive inotropes, usually dobutamine or milrinone. These positive inotropic agents improve hemodynamics and symptoms by increasing intracellular cyclic adenosine monophosphate within the failing heart but have been associated with an increased risk of death and other cardiovascular events. 1,2 Levosimendan is a pharmacological agent that exerts positive inotropic effects by binding to cardiac troponin C in a calcium-dependent manner, sensitizing myofilaments to calcium.3,4 Levosimendan also has vasodilatory proper- Context Because acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival.Objective To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. Design, Setting, and PatientsThe Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, doubleblind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004. Interventions Intravenous levosimendan (n = 664) or intravenous dobutamine (n=663).Main Outcome Measure All-cause mortality at 180 days.Results All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P=.40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (PϽ.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group. ConclusionDespite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. Trial Registration clinicaltrials.gov Identifier: NCT00348504

In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425).

In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

Background Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile. Electronic supplementary material The online version of this article (10.1186/s41927-018-0031-x) contains supplementary material, which is available to authorized users.

O steoblastic metastases occur in advanced cases of prostate cancer and frequently in breast cancer (1). Many factors have been proposed to cause disorganized new bone formation at sites of metastases, including insulin-like growth factors 1 and 2, transforming growth factor (TGF)-␤, prostate-specific antigen, urokinase-type plasminogen activator, fibroblast growth factors (FGF)-1 and -2, bone morphogenic proteins (BMPs), and, in particular, endothelin-1 (ET-1) (2-7).ET-1 is a potent vasoconstrictor that binds to ET A and ET B receptors with the latter functioning in ligand clearance (8,9). ET-1 is produced by and affects bone cells (10-12). It stimulates mitogenesis in osteoblasts, which express both ET A and ET B receptors (13-15). ET-1 can decrease osteoclast activity and motility (16).The prostate expresses ET-1 ligand and receptors (5-7). Primary and metastatic prostate cancers make 6,17,18), which can stimulate autocrine proliferation and potentiate effects of insulin-like growth factors, platelet-derived growth factor, epidermal growth factor, and FGF-2 (5). ET B receptor expression is decreased in prostate cancer (5). Nelson et al. (6) found that plasma ET-1 concentrations were higher in men with advanced prostate cancer with bone metastases compared with men with organ-confined disease (6). ET-1 concentrations did not correlate to tumor burden in bone. Five human prostate cancer cell lines expressed ET-1 messenger RNA, and ET-1 increased BMP-initiated bone formation (6).Breast cancers also express ET-1 and are the next most common cause of osteoblastic metastases. Breast cancer cells can convert preproET-1 to 20). Thus, substantial data implicate ET-1 in the pathogenesis of osteoblastic metastases, but a causal role for ET-1 in bone metastasis has not been directly tested. Questions remain about the importance of ET-1 on bone formation in vivo and whether ET-1 receptor blockade would decrease osteoblastic metastases.We found three human breast cancer cell lines that produce ET-1 and cause osteoblastic bone metastases. We used nude mice inoculated with ZR-75-1 cells to demonstrate a causal role for ET-1 in osteoblastic metastasis. Endothelin A receptor blockade in this model dramatically decreased metastases and tumor burden in bone. Materials and MethodsCells. ZR-75-1 and T47D were from American Type Culture Collection. C. Kent Osborne (San Antonio, TX) provided MCF-7 and MDA-MB-231. ZR-75-1 and T47D cells were grown in RPMI medium 1640; MDA-MB-231 in DMEM; MCF-7 in Iscove's modified Eagle's medium (IMEM); and BT483, BT549, MDA-MB435s, HS578T, MDA-MB-436, MDA-MB-361 PC-3, DU145, LNCaP, and TSU-Pr1 in 1:1 mixture of F12͞DMEM. All media contained 10% FCS, 1% penicillin͞streptomycin, and 1% nonessential amino acids in a 37°C atmosphere of 5% CO 2 ͞95% air. T47D and MCF-7 culture media were supplemented with insulin. At 80% confluence, 250 l of serum-free media was conditioned in 48-well plates for 48 h, and cells were counted. ET-1 and BQ-123 were from American Peptide (Sunnyvale, CA). New Bone Formation ...